Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that regulates the expression of a variety of antioxidant and detoxification genes through an antioxidant-response element. Nrf2 has been shown to protect several types of cells against the acute and chronic injury that accompanies oxidative stress, but its role in osteoclasts remains unclear. In this study, we investigated the role of Nrf2 in osteoclast (OC) differentiation, a process in which reactive oxygen species (ROS) are generated and then participate, using Nrf2-knockout mice. Receptor activator of nuclear factor κB ligand (RANKL)-induced OC differentiation, actin ring formation, and osteoclastic bone resorption were substantially promoted in Nrf2-deficient OC precursor cells compared to wild-type cells. Under both unstimulated and RANKL-stimulated conditions, Nrf2 loss led to an increase in the intracellular ROS level and the oxidized-to-reduced glutathione ratio and a defect in the production of numerous antioxidant enzymes and glutathione. Moreover, pretreatment with N-acetylcysteine or diphenyleneiodonium significantly reduced the OC differentiation and decreased the intracellular ROS level in both Nrf2-deficient and wild-type cells. Pretreatment with sulforaphane and curcumin also inhibited the OC differentiation by activating Nrf2 in part. Nrf2 deficiency promoted the RANKL-induced activation of mitogen-activated protein kinases, including c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38; the induction of c-Fos; and the consequent induction of nuclear factor of activated T cells, cytoplasmic 1, a pivotal determinant of OC differentiation. Our results suggest that Nrf2 probably inhibits RANKL-induced OC differentiation by regulating the cellular redox status by controlling the expression of oxidative response genes, findings that might form the basis of a new strategy for treating inflammatory bone diseases.